Interference of deoxyadenosine with transmembrane signaling events in human T lymphocytes.
Deoxyadenosine (dAdo) has been recognized as the toxic metabolite in the immunodeficiency disease associated with adenosine deaminase (ADA) deficiency. Under ADA deficient conditions, dAdo accumulates intracellularly as deoxyadenosine triphosphate (dATP) which by interference with ribonucleotide reductase, prevents DNA synthesis. Recently, we and others have demonstrated that in cells rendered ADA deficient by treatment with deoxycoformycin, dAdo affects T-cell activation events which precede DNA synthesis, such as interleukin 2 receptor (IL-2R) expression and IL-2 production. Here we have analyzed interference of dAdo with the early events of T-cell activation. It is shown that dAdo affects the mitogen induced phosphatidyl inositol turnover. Furthermore dAdo interferes with increase of intracellular calcium. Deoxycytidine, although capable of preventing intracellular accumulation of dATP, cannot reverse the functional consequences of dAdo treatment. The ability of a cell to increase its cytoplasmic free Ca2+, as induced by ionomycin, is not affected by dAdo. The exact target for this novel effect of dAdo is at the present unknown.
Scharenberg
J G
JG
Department of Immunology, University Hospital for Children and Youth Het Wilhelmina Kinderziekenhuis, Utrecht, The Netherlands.
Rijkers
G T
GT
Akkerman
J W
JW
Staal
G E
GE
Zegers
B J
BJ
D000243:Adenosine Deaminase / Q000172:deficiency; D000328:Adult; D002118:Calcium / Q000097:blood / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D003839:Deoxyadenosines / Q000494:pharmacology*; D003841:Deoxycytidine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D010743:Phospholipids / Q000032:analysis; D010835:Phytohemagglutinins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology
D003839:Deoxyadenosines; D010743:Phospholipids; D010835:Phytohemagglutinins; D003841:Deoxycytidine; D003208:Concanavalin A; D000243:Adenosine Deaminase; D002118:Calcium